Karyopharm Shares Data at ASH 2023 Showing Strong SVR and TSS Durability Observed from Phase 1 Study of Selinexor 60mg and Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Myelofibrosis Patients, with no SVR or TSS Progressions Observed As of the Data Cutoff(1)

Posted on December 13, 2023December 13, 2023 by mpn_admin

Biomarker Data from Phase 1 Study of Selinexor in Combination with Ruxolitinib in Treatment-Naïve Myelofibrosis (MF) Suggestive of Disease Modification

Data Reinforce the Potential for Selinexor in Combination with Ruxolitinib to Become a Novel, First-Line Treatment for JAKi-Naïve Patients with MF

NEWTON, Mass., Dec. 10, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced long-term follow up of treatment-naïve patients with myelofibrosis (MF) who participated in the Phase 1 portion of its study evaluating once-weekly selinexor in combination with ruxolitinib (NCT04562389). The data, featured in an oral presentation at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023), show patients treated with 60mg selinexor, and who achieved ≥35% reduction in spleen volume (SVR35) at week 24, continued to remain in radiographic response. In addition, all patients who achieved TSS50 at Week 24 remained in response as of the data cut-off.

The data included in the oral presentation for ASH 2023 were based on the Phase 1 portion of the Phase 1/3 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with treatment-naïve MF (NCT04562389). As of August 1, 2023, 24 patients had been assigned to either selinexor 40mg (N= 10) or 60mg (N=14), in combination with ruxolitinib. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.

An exploratory biomarker analysis showed a reduction of variant allele frequency (VAF) at week 24 for all three MF driver genes (CALR, MPL, and JAK2) and rapid and sustained reduction of pro-inflammatory cytokine production. Early cytokine reduction at Week 4 was associated with spleen volume reduction (SVR) at Week 24 and was sustained until the end of treatment. The clinical efficacy associated with biomarkers impacting MF biological hallmarks may suggest disease modification.

“The growing body of data from this study suggests that selinexor in combination with ruxolitinib may provide spleen reduction, symptom improvement, long-term durability and disease modification, expanding the benefit this combination may provide to patients with treatment-naïve myelofibrosis, ” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “We’re excited about the potential to change treatment paradigms for these patients – and expand the number of patients who benefit from first-line therapy.”

The safety profile was consistent with previous data cuts with no new safety signals observed as of Aug 1^st.

“The current standard of care is not associated with consistent molecular or pathologic responses,” said Dr. Sri Tantravahi, University of Utah. “The long-term findings are very exciting as they underscore the potential for durable, clinically relevant responses and modification of disease course. The wait for new options has been long and difficult for the myelofibrosis community, and we welcome this important research to help advance the understanding of XPO1 and JAK inhibitor combinations as a meaningful treatment option for patients.”

“We are encouraged by the attention MPNs (Myeloproliferative Neoplasms) are getting in recent years from companies like Karyopharm,” said Kapila Viges, Chief Executive Officer of MPN Research Foundation. “With patients waiting for more answers to these chronic yet serious blood cancers, we look forward to the data readouts at ASH this year. Efforts to develop better therapies and now combinations of therapies bring hope to the myelofibrosis community and open the potential for more options in the treatment paradigm. For patients, options matter.”

About XPOVIO® (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

Navitoclax Combo Significantly Reduces Spleen Volume in Myelofibrosis

Posted on December 13, 2023December 13, 2023 by mpn_admin

December 10, 2023

Silas Inman

Combining navitoclax with ruxolitinib produced significant reductions in spleen volume by at least 35% at week 24 (SVR35W24) compared with ruxolitinib plus placebo but did not lead to significant changes in total symptom score (TSS) in those with myelofibrosis, according to data from the phase 3 TRANSFORM-1 study (NCT04472598) presented during the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

After a median follow-up of 14.9 months (range, 0.0-29.5), navitoclax and ruxolitinib elicited a SVR35W24 for 63.2% of patients compared with 31.5% for placebo plus ruxolitinib, marking a significant overall difference of 31.0% (95% CI, 19.5%-42.5%; P <.0001). At week 24, there was a mean -9.7 change in TSS with navitoclax/ruxolitinib from baseline (95% CI, -11.8 to -7.6) compared with a change of -11.1 for placebo plus ruxolitinib (95% CI, -13.2 to -9.1), which was not statistically significant (P = .2852).

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Naveen Pemmaraju, MD, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. Ruxolitinib alone is a nice drug for symptom improvement, but when you add in a second drug, you’re improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral navitoclax is a BCL-XL, BCL-2, and BCL-W inhibitor, which may impart unique efficacy for myeloproliferative neoplasms (MPN). “It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the navitoclax by itself or even better in combination with the ruxolitinib can overcome JAK resistance and add benefit.”

In the combination arm, navitoclax was administered at a starting dose of 200 mg if platelet counts were above 150 x 10⁹ per liter or, if not, at 100 mg, which was later escalated to 200 mg if tolerated and after platelet counts reached greater than 75 x 10⁹ per liter. This methodology was implemented to avoid thrombocytopenia, which was observed in earlier trials with the agent. Ruxolitinib was administered at the standard dose in each arm, although Pemmaraju noted with necessary dose reductions the relative dose intensity was lower. There were 125 patients in the combination arm and 127 in the control group.

In the combination arm, the median age of patients was 70 years (range, 42-87) compared with 69 years (range, 37-85) in the control group. The time from diagnosis to study entry was 8 months (range, 0.3-181.6) in the combination arm and 6 (range, 0.3-198.8) in the control group. Most patients had primary myelofibrosis, at 50% in the investigational arm and 57% in the control group. Other types included transformed version of myelofibrosis, namely those post polycythemia vera and post-essential thrombocythemia. The median spleen volume at entry was 1441 cm3 (range, 419-8020) in the combination group and 1639 cm3 (range, 219-5664) in the control arm.

The median TSS in the combination arm was 21 (range, 0.1-60.6) compared with 24 (range, 6.7-61.6) in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of SVR35 with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a SVR35 compared with 41.7% with ruxolitinib plus placebo, which was a meaningful 34.6% reduction (95% CI, 23.6%-45.6%; P <.0001). The median time to first SVR35 response was similar between groups, at 12.3 (range, 10.1-48.3) vs 12.4 (range, 11.3-72.3) weeks, for the combination and control arms, respectively. Fewer patients lost SVR35 in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of SVR35 in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any grade adverse effect (AE) was common between arms, with more patients in the combination arm having a grade 3 or higher AE (85% vs 70%). The most common grade 3 or higher AEs in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%), and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious AEs were less common with the combination at 26% compared with 32% for the control arm. AEs that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.² At this time, the agent is not approved.

References

Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620.doi:10.1182/blood-2023-173509
AbbVie presents positive investigational navitoclax combination data in phase 2 REFINE study suggesting anti-fibrosis activity for patients with myelofibrosis. News release. AbbVie. April 12, 2022. Accessed December 10, 2023. https://news.abbvie.com/2022-04-12-AbbVie-Presents-Positive-Investigational-Navitoclax-Combination-Data-in-Phase-2-REFINE-Study-Suggesting-Anti-Fibrosis-Activity-for-Patients-with-Myelofibrosis

Study yields ‘encouraging’ preliminary data for navitoclax combination in myelofibrosis

Posted on December 13, 2023December 13, 2023 by mpn_admin

December 11, 2023

Key takeaways:

Navitoclax plus ruxolitinib led to improvement in spleen volume reduction in patients with untreated myelofibrosis.
Adverse events of thrombocytopenia and anemia appeared common but manageable.

SAN DIEGO — Navitoclax added to ruxolitinib led to a significant improvement in spleen volume reduction compared with placebo among patients with untreated myelofibrosis, study results presented at ASH Annual Meeting and Exposition showed.

Findings from the phase 3 TRANSFORM-1 study suggest the combination therapy has a manageable safety profile that appeared consistent with the use of both agents in previous studies, according to researchers.

“The is the first randomized trial in JAKi-naive [myelofibrosis] with a navitoclax and ruxolitinib combination, which led to a in spleen volume reduction 35% at week 24 twice as high as placebo plus ruxolitinib, with similar symptom response despite a lower average dose of ruxolitinib,” Naveen Pemmaraju, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation.

Background and methodology

The double-blind TRANSFORM-1 study assessed the efficacy and safety of navitoclax (AbbVie) — and investigational Bcl-2 inhibitor — plus the JAK2 inhibitor ruxolitinib (Jakafi, Incyte) compared with placebo plus ruxolitinib among adults with JAK2 inhibitor-naive myelofibrosis.

Inclusion criteria included adults with intermediate- or high-risk myelofibrosis with measurable splenomegaly, evidence of myelofibrosis-related symptoms, no prior JAK2 inhibitor treatment, and an ECOG performance score less than or equal to 2.

Researchers randomly assigned patients in a 1:1 ratio to ruxolitinib plus either navitoclax or placebo.

Spleen volume reduction 35% at week 24 served as the study’s primary efficacy endpoint. Secondary endpoints included change in total symptom score at week 24, spleen volume reduction 35% at any time, duration spleen volume reduction 35%, anemia response, reduction in marrow fibrosis, OS, leukemia-free survival, reduction in PROMIS Fatigue scale and improvement in EORTC QLQ-C30 physical functioning scale.

The study included 252 patients (125 received navitoclax and ruxolitinib, 127 received placebo plus ruxolitinib; median age, 69 years; 57% male) with a median follow-up of 14.9 months (0 – 29.5 months).

Results and next steps

Researchers reported that 79 patients (63.2%) in the investigative arm achieved spleen volume reduction 35% at week 24, compared with 40 patients (31.5%) in the control arm, thus meeting the study’s primary efficacy endpoint. Additionally, researchers noted that 96 patients (77%) in the investigative arm achieved spleen volume reduction 35% at any time, whereas 53 patients (42%) did so in the control arm.

Median duration of spleen volume reduction 35% had not been reached in the investigative arm compared with 19.4 months (95% CI, 16.8 months to not yet reached) in the control arm.

Researchers observed grade 3 or higher adverse events among 85% of patients in the navitoclax arm and for 70% of patients in the placebo arm. The most common adverse events among patients receiving navitoclax included thrombocytopenia, anemia, diarrhea, and neutropenia.

Additionally, 26% of patients in the navitoclax arm and 32% of patients in the placebo arm experienced serious adverse events, including anemia, thrombocytopenia and neutropenia.

With navitoclax treatment, adverse events led to a dose reduction of the agent in 101 patients (81%) and treatment interruption in 87 patients (70%).

Among enrolled patients, 83 (33%) discontinued study treatment. The most common reason for discontinuation included adverse events (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). Thirteen patient deaths occurred in each study arm.

“Adverse events of thrombocytopenia, anemia and neutropenia were common but manageable with dose modification without any clinically significant sequelae,” Pemmaraju said. “Preliminary data are encouraging and additional evaluations are ongoing to assess additional outcomes of overall survival and responses in subgroups.”

Source:

Pemmaraju N, et al. Abstract 620. Presented at: ASH Annual Meeting and Exhibition; Dec. 5-9, 2023; San Diego.

One Patient’s Point of View on “Living” with Myelofibrosis

Posted on November 13, 2019November 14, 2019 by mpn_admin

David told his story at the Cleveland MPN Patient Program in November

On a beautiful fall day in late August 2013, I received a call that changed the course of my life. The voice on the other end told me that they had reviewed my blood counts and determined that I had some sort of leukemia. They had pre-admitted me to the local hospital to meet an oncologist and have the necessary tests. After about two weeks I received my diagnosis of Primary Myelofibrosis, Intermediate 1. I was told that treatment options were limited and the only true cure was allogeneic bone marrow transplan

It is tempting to focus all our energies on our hope in medical interventions. But diagnosis brings fear, denial, anger, & depression. These impact your relationships and can throw you into a downward spiral. Being diagnosed with a life-threatening disease like an MPN is an existential challenge. It raises all the questions: Why are we here? What is life about? What lies beyond this life? How you answer these questions will affect how you deal with your disease and its physical effects.

We are all tempted to be sad and maybe even angry. But you do not have to give in to the negative. You can choose to respond with a positive attitude.

My diagnosis has changed the course of my life – but for the better. Because of myelofibrosis, I realized that I was spending far too much of my time and energy focused on some sort of future achievement. I was super-busy every day and the days passed in a blur. But myelofibrosis woke me up to the truth that life is not about some future achievement. Life is about today. Since my diagnosis, I have come to have a heightened enjoyment of the simple pleasures of daily living.

These last six years have been wonderful and I have enjoyed them more because of my disease. My son and his wife have been kind enough to give us two new grandchildren in the past four years – and I am making the most of that. I’ve made many good friends in the MPN community. I took up motorcycle riding. The more aware I am of my mortality – the more I savor every experience of life.

Your life only comes one day at a time. Today is the day you have – make it into something good. Refuse to let an uncertain future rob you of today’s joys.

David shared his story in the MPN Community Connection Newsletter click here to view

David is the support group coordinator for the northern Pennsylvania/Ohio area, if you are interested in participating you can contact us for more information. Click here to contact us.